A vaccine involves the administration of an agent to an individual which willstimulate the immune system to react against the "foreign" components of thevaccine. The vaccine can be administered into the skin, muscle, intraorally, orintravenously. The foreign components of the vaccine are known as "antigens". The end result of a vaccination procedure is to develop immunity in the individualso that a subsequent exposure to the antigen(s) will evoke a response to eliminateor destroy the antigen(s). Vaccines have been highly effective in protecting people from infectiousorganisms. The first successful vaccination procedure was described by EdwardJenner in the 1790's. He observed that milkmaids appeared to be protected fromdeveloping small pox. He theorized that their exposure to the cox pox virus madethem immune to infection by the small pox virus, which was very similar to thecox pox virus. He went on to introduce the cox pox virus into humans and foundthat they were protected against small pox. This demonstrated that the immunesystem can be recruited to react to a particular infectious organism; and,eventually eliminated small pox as a public health problem. Vaccinations forbacterial and viral infectious agents are now routinely used for: influenza viruses,measles, chicken pox, polio, pneumococcal bacteria, and hepatitis viruses. Thereis a tremendous effort currently being conducted to identify an effective HIVvaccine. Because of the success in immunizing individuals against certain infectiousorganisms, it has been the dream of clinicians and scientists to develop effectivevaccines against cancers. One of the earliest steps in that direction was pioneeredby William B. Coley in the 1890's. He was a general surgeon in New York City whoobserved that occasional patients who developed an infection in the vicinity oftheir cancer have reductions in the size of their tumors. He took the bold step oftaking live bacterial organisms and directly injecting them into growing soft tissuetumors. To his amazement, some of these tumors shrank after developing a briskinflammatory response. It was theorized that the immune system was activatedby the inoculation of the bacteria and subsequently caused its destruction. Thiswas the first observation that the immune system could be activated to causetumor regression. Coley spent the rest of his career trying to isolate the toxinsproduced by the bacteria which he felt were responsible for the antitumor effects.

What are the different types of cancer vaccines?

Coley initiated a series of studies attempting to activate the immune systemutilizing bacterial agents which included erysipelas streptococcus and Serratiamarcescens. Other bacterial agents which have been examined by otherinvestigators included bacillus Calmette-Guérin (BCG) and Corynebacteriumparvum (C. parvum). This form of therapy attempts to activate the immunesystem in a non-specific fashion. Unfortunately, several clinical trials evaluatingthese non-specific agents or their products proved ineffective. However, many ofthese bacterial agents are now being combined with "tumor-associated" antigens(TAAs) as a method to induce specific immunity to tumors. Tumor-associatedantigens are structures (ie., proteins, enzymes or carbohydrates) which arepresent on tumor cells and relatively absent or diminished on normal cells. Byvirtue of being fairly unique to the tumor cell, TAAs provide targets for theimmune system to recognize and cause their destruction.

The nature of tumor-associated antigens were unknown for a long time. Many ofthe initial clinical studies of specific tumor vaccines involved utilizing the tumorcell as a source of TAAs. These tumor cells were obtained from the patient andrendered non-viable by irradiation or killing the tumor cells so that only themembrane fragments remain for use as a vaccine. The tumor cell preparation wasthen combined with an "adjuvant" prior to inoculation in the skin. An adjuvant isan agent, such as BCG, which will augment the immune response to TAAs.

Many TAAs have now been identified and represent a diverse array of structuresassociated with tumor cells. For example, some cancer cells manufacture andsecrete protein structures not normally produced by other cells. Examplesinclude: carcinoembryonic antigen (CEA) produced by colon cancers and otheradenocarcinomas (ie., breast, lung, gastric, and pancreas cancers); prostatespecific antigen (PSA) produced by prostate cancers; and alpha-fetoprotein (AFP)produced by liver cancers (a.k.a. hepatomas). Clinical trials are underway tovaccinate patients to these secreting proteins in an attempt to eradicate tumor.

Several TAAs expressed by tumors represent normal components of cells fromwhich the tumor originates. For example, PSA is made by prostate cancer cellsbut also by normal prostate cells. Hence, immunity to PSA will hopefully impacton prostate cancer cells but also may result in an "auto-immunity" to the prostategland. This is dramatically seen with the immune treatment of melanoma, amalignant skin cancer. Melanoma tumors express TAAs which are also expressedby normal melanosomes. Melanosomes are skin cells which make pigment andgive coloration to the skin. It has been reported that patches of "vitiligo" ordepigmentation can occur in individuals who undergo a tumor response of theirmelanoma with immune treatments (either vaccination or other immunetherapies). This is an example of an autoimmune phenomenon whichdemonstrates that an immune response can be mounted against normal "self"antigens which also results in tumor regression.

Many of the gene therapies involving cancer represent a form of cancer vaccines. The ability to introduce genes into cells is known as gene transfer. Investigatorshave used these techniques to introduce genes into tumor cells to make themmore reactive to the patient's immune system. These genes contain the buildingblocks for immune hormones (ie., interferon, interleukin-2 (IL-2),granulocyte-macrophage colony-stimulating factor (GM-CSF), etc.) or otherstimulatory proteins which have been found to enhance the effectiveness of thesevaccines in animal studies.

Another area of active research in cancer vaccines has been with a unique cellknown as the dendritic cell (DC). Dendritic cells have been found to be necessaryto trigger the immune response to foreign antigens. DCs work by taking upantigens and processing them into a form where other cells of the immune system(ie., T cells) can respond to them. DCs can be removed from the blood stream,grown in the laboratory, and then exposed (a.k.a. pulsing) to tumor antigen inculture plates. When these "pulsed" DCs are injected back into the cancer-bearingindividual, an immune response is generated causing subsequent tumorshrinkage. These latter findings have been observed in animal studies and arenow being tested in clinical trials.

Examples of different forms of tumor antigens and adjuvants are listed in Table 1.

Tumor Antigens

Description

Autologous tumor cells

Whole cells or portions (a.k.a. lysates) of cellsobtained from the patient being treated.

Allogeneic tumor cells

Whole cells or portions of cells obtained from differentpatient(s). Common shared antigens exist among tumors of the samehistology.

Chemotherapeutic agent which is thought to reducetumor-induced suppression when given in low doses.

Are any vaccines approved for clinical use?

There are no cancer vaccines which have been approved by the United StatesFood and Drug Administration for routine use. Currently, cancer vaccines areexperimental and are being administered in the setting of clinical trials. Most ofthese clinical trials involve patients with advanced cancers who have no otherstandard treatments such as chemotherapy, surgery or radiation available tothem.

To date, melanoma is the tumor type where most of the clinical studies have beenperformed with vaccines. There are more TAAs which have been identified formelanoma tumors compared to any other cancer. There are severalmulti-institutional trials evaluating tumor vaccines versus interferon-alpha in thetreatment of melanoma which has metastasized to local draining lymph nodes. After surgical removal of the disease, standard therapy involves administration ofinterferon-alpha for 1 year. These trials involve randomizing patients to receiveinterferon-alpha or a cancer vaccine after surgery. Since vaccines are associatedwith minimal toxicity, any results of these trials which demonstrate similar curerates in both groups will be beneficial for future patients since interferon-alphahas a significant toxicity profile.

Other vaccine studies in melanoma involve patients with more advancedmelanoma (ie. Stage IV where melanoma has metastasized beyond the draininglymph nodes). These vaccine studies generally involved a single institution wherea specific researcher is testing a vaccine he or she has developed. These vaccinesmay involve tumor cells, tumor peptides, dendritic cells "pulsed" with TAAs, orgene-modified tumor cells administered along with various adjuvants.

Studies are being conducted in advanced cancers such as breast cancer,colorectal cancer, ovarian cancer, cervical cancer, and prostate cancer utilizingtumor antigens identified in the above table. For the most part, these are phase Ior II studies to determine the toxicity profile of the vaccine, and to measure anyimmunologic or tumor responses. Phase I studies are designed to test differentdoses of the vaccine and determine what the toxicity may be with the differentdoses. Phase II studies are designed to test a set dose of the vaccine anddetermine what response rates are associated with that particular regimen.

How can I find out if I qualify for a vaccine?

If you have a history of a cancer which has been successfully removed andtreated with standard therapies, chances are you are not a candidate for a cancervaccine. If you have an advanced cancer which has failed standard treatments,there may be research vaccine trials for which you are eligible. One source ofinformation is with the National Cancer Institute (NCI) Trials Database which is alist and description of many clinical trials across the country. This is known as thePDQ listing and can be accessed via the Internet (http://cancertrials.nci.nih.gov/)or calling Cancer Information Service 1-800-4-CANCER. Another source ofinformation would be to contact your nearest NCI-designated cancer center (i.e.University of Michigan Comprehensive Cancer Center). There are approximately 30of these centers located across the country. These centers are reviewed andcertified by the NCI for the quality of their clinical research. Each NCI-designatedcancer center has an information line or website which will provide informationabout their clinical studies.

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